Inverting Small Molecule–Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism

Fluorinated motifs have a venerable history in drug discovery, but as C(sp3)−F‐rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5‐stereotriad, in the substra...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Angewandte Chemie International Edition 2019-08, Vol.58 (32), p.10990-10994
Hauptverfasser: Bentler, Patrick, Bergander, Klaus, Daniliuc, Constantin G., Mück‐Lichtenfeld, Christian, Jumde, Ravindra P., Hirsch, Anna K. H., Gilmour, Ryan
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Fluorinated motifs have a venerable history in drug discovery, but as C(sp3)−F‐rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5‐stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well‐defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F−C−C−X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes. Fluorine effect: Installation of a 1,3,5‐stereotriad in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. The transformation provides facile access to optically active, stereochemically well‐defined organofluorine compounds.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201905452